Doxycycline Tablets

Type of Posting Revision Bulletin

Posting Date 30Mar2018

Official Date 01Apr2018

Expert Committee Chemical Medicines Monographs 1

Reason for Revision Compliance In accordance with the Rules and Procedures of the 2015–2020 Council of Experts, the Chemical Medicines Monographs 1 Expert Committee has revised the Doxycycline Tablets monograph. The purpose of the revision is to add Dissolution Test 2 for a generic product approved by the FDA. A Labeling section was also added.

The Doxycycline Tablets Revision Bulletin supersedes the currently official monograph. The Revision Bulletin will be incorporated in USP 42–NF 37.

Should you have any questions, please contact Praveen Pabba, Ph.D. Scientific Liaison (301-816-8540 or pkp@usp.org).

C197770-M5071-CHM12015, rev. 00 20180330

Doxycycline Tablets

DEFINITIONDoxycycline Tablets contain NLT 90.0% and NMT 120.0%

of the labeled amount of doxycycline (C22H24N2O8).

IDENTIFICATION• A. The retention time of the major peak of the Sample

solution corresponds to that of the Standard solution, asobtained in the Assay.

• B. The UV spectrum of the major peak of the Samplesolution corresponds to that of the Standard solution, asobtained in the Assay.

ASSAY• PROCEDURE

Protect solutions containing doxycycline from light.Solution A: Transfer 3.1 g of monobasic potassium

phosphate, 0.5 g of edetate disodium, and 0.5 mL of triethylamine to a 1000-mL volumetric flask. Add about850 mL of water and mix. Dilute with water to volumeand adjust with 1 N sodium hydroxide to a pH of 8.5± 0.1.

Solution B: MethanolMobile phase: See Table 1.

Table 1

Time(min)

Solution A(%)

Solution B(%)

0.0 90 10

2.0 90 10

4.0 60 40

6.0 90 10

9.0 90 10

Diluent: 0.01 N hydrochloric acidStandard solution: 0.12 mg/mL of USP Doxycycline

Hyclate RS in Diluent. Sonicate as needed to dissolve.Sample solution: Nominally 0.1 mg/mL of doxycycline

from NLT 20 Tablets prepared as follows. Transfer asuitable portion of finely powdered Tablets to a suitablevolumetric flask. Add 50% of the final volume of Diluent,dissolve, dilute with Diluent to volume, and mix well.Centrifuge a portion of the solution and use thesupernatant. [NOTE—The use of a centrifuge speed at3,000 rpm for 10 min may be suitable. ]

Chromatographic system(See Chromatography á621ñ, System Suitability.)Mode: LCDetector: UV 270 nm. For Identification B, a diode array

detector may be used in the wavelength range of 200–400 nm.

Column: 2.1-mm × 5-cm; 1.7-µm packing L7. [NOTE—A1.7-µm guard column with packing L7 was used duringmethod validation. ]

Column temperature: 60°Flow rate: 0.6 mL/minInjection volume: 5 µL

System suitabilitySample: Standard solutionSuitability requirements

Tailing factor: NMT 1.5Relative standard deviation: NMT 2.0%

AnalysisSamples: Standard solution and Sample solution

Calculate the percentage of the labeled amount ofdoxycycline (C22H24N2O8) in the portion of Tabletstaken:

Result = (rU/rS) × (CS/CU) × P × F × 100

rU = peak response from the Sample solutionrS = peak response from the Standard solutionCS = concentration of USP Doxycycline Hyclate RS

in the Standard solution (mg/mL)CU = nominal concentration of doxycycline in the

Sample solution (mg/mL)P = potency of doxycycline in USP Doxycycline

Hyclate RS (µg/mg)F = conversion factor, 0.001 mg/µg

Acceptance criteria: 90.0%–120.0%

PERFORMANCE TESTS

Change to read:

• DISSOLUTION á711ñ▲Test 1▲ (RB 1-Apr-2018)

Medium: 0.01 N hydrochloric acid; 900 mLApparatus 2: 75 rpmTime: 60 minStandard solution: 0.01 mg/mL of doxycycline from USP

Doxycycline Hyclate RS in MediumSample solution: Pass a portion of the solution under

test through a suitable filter. Dilute a portion of thefiltrate with Medium to a concentration that is similar tothat of the Standard solution.

Instrumental conditions(See Ultraviolet-Visible Spectroscopy á857ñ.)Mode: UVAnalytical wavelength: 268 nmCell: 1 cmBlank: Medium

AnalysisSamples: Standard solution and Sample solutionDetermine the percentage of the labeled amount of

doxycycline (C22H24N2O8) dissolved:

Result = (AU/AS) × (CS/L) × V × P × 100

AU = absorbance of the Sample solutionAS = absorbance of the Standard solutionCS = concentration of USP Doxycycline Hyclate

RS in the Standard solution (mg/mL)L = label claim (mg/Tablet)V = volume of Medium, 900 mLP = potency of doxycycline in USP Doxycycline

Hyclate RS (µg/mg)

Tolerances: NLT 85% (Q) of the labeled amount ofdoxycycline (C22H24N2O8) is dissolved.

▲Test 2: If the product complies with this test, the labelingindicates that it meets USP Dissolution Test 2.Protect solutions containing doxycycline from light.Medium: 0.01 N hydrochloric acid; 900 mLApparatus 2: 75 rpmTime: 15 minStandard solution: 0.01 mg/mL of doxycycline from USP

Doxycycline Hyclate RS in MediumSample solution: Pass a portion of the solution under

test through a suitable filter. Dilute a portion of thefiltrate with Medium to a concentration that is similar tothat of the Standard solution.

Revision BulletinOfficial April 1, 2018

Official Monographs / Doxycycline 1

© 2018 The United States Pharmacopeial Convention All Rights Reserved.C197770-M5071-CHM12015, rev. 00 20180330

Instrumental conditions(See Ultraviolet-Visible Spectroscopy á857ñ.)Mode: UVAnalytical wavelength: 268 nmCell: 1 cmBlank: Medium

AnalysisSamples: Standard solution and Sample solutionDetermine the percentage of the labeled amount of

doxycycline (C22H24N2O8) dissolved:

Result = (AU/AS) × (CS/L) × D × V × P × F × 100

AU = absorbance of the Sample solutionAS = absorbance of the Standard solutionCS = concentration of USP Doxycycline Hyclate

RS in the Standard solution (mg/mL)L = label claim (mg/Tablet)D = dilution factor for the Sample solution, if

applicableV = volume of Medium, 900 mLP = potency of doxycycline in USP Doxycycline

Hyclate RS (µg/mg)F = conversion factor, 0.001 mg/µg

Tolerances: NLT 80% (Q) of the labeled amount ofdoxycycline (C22H24N2O8) is dissolved.▲ (RB 1-Apr-2018)

• UNIFORMITY OF DOSAGE UNITS á905ñ: Meet therequirements

IMPURITIES• ORGANIC IMPURITIES

Protect solutions containing doxycycline from light.Mobile phase, Diluent, and Chromatographic

system: Proceed as directed in the Assay.System suitability stock solution 1: 1 mg/mL each of USP

Doxycycline Related Compound A RS and USPMethacycline Hydrochloride RS in Diluent

System suitability stock solution 2: 1.2 mg/mL of USPDoxycycline Hyclate RS in Diluent

System suitability solution: Transfer 5 mL of Systemsuitability stock solution 2 to a 25-mL volumetric flask, heaton a steam bath for 60 min, and evaporate to dryness ona hot plate, taking care not to char the residue. Dissolvethe residue in Diluent, add 0.5 mL of System suitabilitystock solution 1, and dilute with Diluent to volume. Passthe solution through a suitable filter and use the filtrate.This solution contains a mixture of 4-epidoxycycline,doxycycline related compound A, methacycline, anddoxycycline. [NOTE—The solution is stable up to 14 dayswhen stored in a refrigerator at 2°–8°. ]

Standard solution: 7.0 µg/mL of USP Doxycycline HyclateRS in Diluent

Sample solution: Nominally 2.0 mg/mL of doxycyclinefrom NLT 20 Tablets prepared as follows. Transfer asuitable portion of finely powdered Tablets to a suitablevolumetric flask. Add 50% of the final volume of Diluent,dissolve, dilute with Diluent to volume, and mix well.Centrifuge a portion of the solution and use thesupernatant. [NOTE—The use of a centrifuge speed at3,000 rpm for 10 min may be suitable. ]

System suitabilitySamples: System suitability solution and Standard solutionSuitability requirements

Resolution: NLT 1.5 between methacycline and 4-epidoxycycline; NLT 1.5 between 4-epidoxycycline anddoxycycline related compound A; NLT 2.0 betweendoxycycline related compound A and doxycycline,System suitability solution

Relative standard deviation: NMT 5.0% for thedoxycycline peak, Standard solution

AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of each impurity in the portion

of Tablets taken:

Result = (rU/rS) × (CS/CU) × P × F × 100

rU = peak response of each impurity from theSample solution

rS = peak response of doxycycline from theStandard solution

CS = concentration of USP Doxycycline Hyclate RSin the Standard solution (mg/mL)

CU = nominal concentration of doxycycline in theSample solution (mg/mL)

P = potency of doxycycline in USP DoxycyclineHyclate RS (µg/mg)

F = conversion factor, 0.001 mg/µg

Acceptance criteria: See Table 2. Disregard peaks lessthan 0.1%.

Table 2

Name

RelativeRetention

Time

AcceptanceCriteria,

NMT (%)

Methacyclinea, b 0.64 —

4-Epidoxycyclinec 0.79 1.5

Doxycycline relatedcompound A(6-epidoxycycline)b, d 0.88

—

Doxycycline 1.0 —

Any individualunspecified impurity — 0.3

Total impurities — 2.5

a (4S,4aR,5S,5aR,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-2-naphthacenecarboxamide.b Process impurities that are controlled in the drug substance are not to bereported. They are not to be included in total impurities. They are listed herefor information only.c (4R,4aR,5S,5aR,6R,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide. Main degradation product.d (4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide.

ADDITIONAL REQUIREMENTS• PACKAGING AND STORAGE: Preserve in tight, light-resistant

containers. Store at controlled room temperature.

Add the following:

▲• LABELING: When more than one Dissolution test is given,the labeling states the test used only if Test 1 is notused.▲ (RB 1-Apr-2018)

• USP REFERENCE STANDARDS á11ñUSP Doxycycline Hyclate RSUSP Doxycycline Related Compound A RS

2 Doxycycline / Official Monographs Revision BulletinOfficial April 1, 2018

© 2018 The United States Pharmacopeial Convention All Rights Reserved.C197770-M5071-CHM12015, rev. 00 20180330

[NOTE—May be available as a free base or ahydrochloride salt.]

(4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide.

C22H24N2O8 444.43(4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-1,4,4a,

5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide, monohydrochloride.

C22H24N2O8 · HCl 480.13USP Methacycline Hydrochloride RS

Revision BulletinOfficial April 1, 2018

Official Monographs / Doxycycline 3

© 2018 The United States Pharmacopeial Convention All Rights Reserved.C197770-M5071-CHM12015, rev. 00 20180330